1. Field of the Invention
The present invention relates to novel metal complex glycogen synthase kinase 3 inhibitors, methods for making such compounds, and methods for using such compounds for treating diseases and disorders mediated by glycogen synthase kinase 3 activity.
2. Description of the Background
The development of high affinity and specific compounds for a given protein target is a great and often unsolved challenge. For example, the human genome codes for more than 500 protein kinases and many of them constitute major drug targets since mutations and dysregulations in protein kinases play important roles in disease. Yet, not a single existing kinase inhibitor is completely specific for a particular kinase. The development of small molecules that perturb specific protein functions is of great importance for probing biological processes and ultimately for the development of potent and safe drugs.
Medicinal chemistry is predominately focused on organic chemistry. In the cases where metals are employed, it is for their reactivity and or imaging properties (see FIG. 1). Applicant explores a different direction and bridges the fields of organic and inorganic medicinal chemistry by using metal centers as chemically inert structural scaffolds for drug design. Such metal-ligand assemblies allow convergent and economical synthetic approaches and give access to structural motifs that differ from purely organic molecules.
Further, medicinal chemistry is predominately focused on the design of organic molecules, whereas the incorporation of inorganic components into drugs is much less investigated. Furthermore, in almost all metallopharmaceuticals, the metal ion possesses a reactive feature. We have found that certain organometallic and inorganic compounds are useful as structural scaffolds for enzyme inhibition. Such metal-ligand assemblies allow convergent synthetic approaches and give access to structural motifs that differ from purely organic molecules. Nature makes extended use of metals not only for their reactivity but also for structural purposes, as for example in zinc binding aspartate transcarbamoylase and zinc finger domains, or the calcium binding protein calmodulin.
Protein kinases regulate most aspects of cellular life and are one of the main drug targets. An example is the microbial alkaloid staurosporine, which is a very potent, but relatively nonspecific inhibitor of many protein kinases. Many staurosporine derivatives and related organic compounds with modulated specificities have been developed and several are in clinical trials as anticancer drugs. They all share an indolo[2,3-α]carbazole aglycon which binds to the ATP binding site and can hydrogen bond with two conserved amino acids. For this class of inhibitors, specificity for a particular protein kinase can be achieved by the moiety which is attached to the indole nitrogen atoms.
Glycogen synthase kinase 3 (GSK3) is a serine/threonine kinase for which two isoforms, α and β, have been identified. Woodgett, Trends Biochem. Sci., 16:177-81 (1991). Both GSK3 isoforms are constitutively active in resting cells. GSK3 was originally identified as a kinase that inhibits glycogen synthase by direct phosphorylation. Upon insulin activation, GSK3 is inactivated, thereby allowing the activation of glycogen synthase and possibly other insulin-dependent events, such glucose transport. Subsequently, it has been shown that GSK3 activity is also inactivated by other growth factors that, like insulin, signal through receptor tyrosine kinases (RTKs). Examples of such signaling molecules include IGF-1 and EGF. Saito et al., Biochem J., 303:27-31 (1994); Welsh et al., Biochem. J.294:625-29 (1993); and Cross et al., Biochem. J., 303:21-26 (1994).
Despite the apparent promise of glycogen synthase kinase 3 modulators as a target for controlling disorders, very few of such compounds appear in the patent database. Examples of these are pyrazole compositions useful as glycogen synthase kinase 3 inhibitors, especially as inhibitors of aurora-2 and GSK-3, for treating diseases such as cancer, diabetes, and Alzheimer's disease. Another example is that of pyrazine based inhibitors of glycogen synthase kinase 3, for treating diseases such as diabetes, Alzheimer's disease and other neurodegenerative disorders, obesity, atherosclerotic cardiovascular disease, essential hypertension, polycystic ovary syndrome, syndrome X, ischemia, traumatic brain injury, bipolar disorder, immunodeficiency or cancer.
Thus, there is a significant need in the art for more specific and effective glycogen synthase kinase 3 inhibitors, which can be targeted to specific tissues and/or disease states. Applicants have developed metal complexes that target the ATP binding site of glycogen synthase kinase 3. Additional ligands in the coordination sphere of the metal ion undergo additional specific contacts with other parts of the active site, giving metal complex binders with high affinity and specificity for glycogen synthase kinase 3.